Camptothecin (Chem. Abstracts Registry No. 7689-03-4) is a naturally occurring compound found in Camptotheca acuminata (Nyssaceae) which has antileukemic and antitumor properties. Numerous camptothecin analogs having like properties are known, examples being those described in U.S. Pat. No. 4,894,456 to Wall et al. and European Patent Application No. 0 325 247 of Yaegashi et al.
A number of linear syntheses for camptothecin are known. Several routes are reviewed in Natural Products Chemistry, Vol. 2, 358-361 (K. Nakanishi, T. Goto, S. Ito, S. Natori and S. Nozoe eds.) and in J. Cai and C. Hutchinson, Camptothecin, in The Alkaloids, Vol. XXI, 101-137 (Academic Press 1983). The biosynthesis of camptothecin is described in Natural Products Chemistry, Vol. 3, 573-574 (K. Nakanishi et al. eds.). A recent synthetic route is described in U.S. Pat. No. 4,894,456 to Wall et al. (see also references cited therein).
Parallel syntheses, in which two synthetic paths are followed separately and the products thereof combined to form the final product, generally provide higher yields than linear syntheses. Parallel syntheses for camptothecin and camptothecin analogs is disclosed in U.S. Pat. No. 5,162,532 and U.S. Pat. No. 5,212,317. These patents disclose syntheses in which the camptothecin or camptothecin analog is produced via an intermediate of Formula IV: ##STR5## wherein R may be loweralkyl; R.sub.1 may be H, loweralkyl, loweralkoxy, or halo; R.sub.2, R.sub.3, R.sub.4 and R.sub.5 may each independently be H, amino, hydroxy, loweralkyl, loweralkoxy, loweralkylthiol, di(loweralkyl)amino, cyano, methylenedioxy, formyl, nitro, halo, trifluoromethyl, aminomethyl, azido, amido, hydrazino, or any of the twenty standard amino acids bonded to the A ring via the amino-nitrogen atom; X is Br or I; and Y is H. The intermediate of Formula IV is then cyclized by an intramolecular Heck reaction in a polar aprotic solvent in the presence of a palladium catalyst to yield camptothecin or an analog thereof.